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Science : Why cold turkey is molecular murder

By Bob Holmes

Santa Cruz

THE BRAINS of mammals produce a molecule that blocks the action of morphine
and other opiate drugs, neurobiologists in Oregon have found. The discovery may
be the key to why morphine tolerance develops in patients receiving the drug for
pain relief and why heroin addicts suffer withdrawal symptoms.

The molecule, known as orphanin FQ, or OFQ, is one of four substances
produced by the brain that are chemically related to morphine, and known as
opioids. The other three, collectively known as endorphins, play roles in
blocking pain sensations and in mediating pleasure and reward pathways in the
brain. When David Grandy and his colleagues began looking at OFQ, they expected
it to be another painkiller. “It turned out it was anything but,” says Grandy, a
molecular neurobiologist at Oregon Health Sciences University in Portland.

In a paper published in the 25 October issue of Neuroscience (vol
75, p 333), Grandy’s team reports that OFQ blocks morphine’s painkilling
activity. Mice given a shot of morphine usually take several seconds longer than
undrugged mice to notice the pain when their tails are dipped into hot water.
But after the researchers injected OFQ into the brains of morphine-doped mice,
they proved just as quick as untreated mice at pulling out their tails.

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In further experiments, Grandy found that mice given opiates over long
periods have higher levels of OFQ in their brains. Increased production of OFQ
in the presence of morphine may explain why patients taking the drug for pain
relief develop a tolerance to it. If so, it might eventually be possible to find
drugs that block the OFQ system and thus prevent patients from developing
tolerance.

In other experiments, Grandy says he has found that mice injected with large
doses of OFQ develop what look like drug withdrawal symptoms—shaking,
diarrhoea and squinting eyes. He believes high levels of opiates such as
morphine and heroin prompt the brain to pump out more OFQ to offset them. If
drugs are then removed, he speculates, the sudden excess of OFQ may produce the
symptoms of withdrawal.